Fatty liver has become a major cause of liver disease, and causes of fatty liver disease include excess consumption alcohol, non-alcohol mediated metabolic abnormalities, and viral infections. For example in the US, more than 10% of people abuse or are dependent on alcohol, and more than 90% of people consuming excess alcohol develop alcoholic fatty liver disease (AFLD). Non-alcoholic fatty liver disease (NAFLD) is a serious health problem and gaining increasing recognition as a pathobiological component of obesity, type 2 diabetes, and metabolic syndrome. The worldwide prevalence of NAFLD is presently estimated at 30% of the general population, and it affects majority (up to 75%) of patients with obesity and type 2 diabetes (1, 2). NAFLD generally refers to a spectrum of liver damage ranging from simple fatty liver (hepatic steatosis), with benign prognosis, to a potentially progressive form, non-alcoholic steato-hepatitis (NASH), which may lead to liver fibrosis and cirrhosis (3). If untreated, NAFLD may lead to liver dysfunction, cirrhosis and its complications (eg. gastro-intestinal hemorrhage, ascites, etc), end-stage liver disease, need for liver transplantation. It is often associated with increased risk for developing cardiovascular disease resulting in increased morbidity and mortality. The clinical diagnosis of NAFLD is usually made based on clinical history and laboratory findings including, high transaminase levels, elevated body mass index (BMI), ultrasound evidence of fat, and features of metabolic syndrome. However, a liver biopsy is required to determine the severity of the disease and presence of NASH, and to assess the degree of fibrosis (4).
Despite its severity and prevalence in patients with obesity, type 2 diabetes, and metabolic syndrome, little is known about the pathogenesis of NAFLD and treatment modalities. Excessive accumulation of triglycerides in hepatocytes is the hallmark of NAFLD, which is strongly associated with hepatic insulin resistance (5-7). Increased triglyceride synthesis has been shown in fatty livers that accompany obesity and type 2 diabetes in humans and mice (8). Using animal models, it was shown that hepatic fat accumulation leads to hepatic insulin resistance by stimulating gluconeogenesis and activating PKC-ε and JNK1 signaling pathways (2). In regards to understanding the pathogenesis of NAFLD, several studies focused on whether hepatic steatosis plays any direct causal role in progression to advanced disease NASH or simply an innocent bystander in the pathogenesis of NAFLD. A two-hit hypothesis has been proposed to understand the pathogenesis of NAFLD: first hit includes excess fat accumulation in the liver, and second hit consist of oxidative stress and lipid peroxidation with increased generation of inflammatory cytokines (8-10). Several studies indicate that hepatic steatosis is a risk factor for NASH and fibrosis, and implicate steatosis as a direct contributor to the progressive NASH and fibrosis (reviewed in 9-12).
Currently, there are no established and recommended pharmacologic agents available for the treatment for NAFLD. Modifications of risk factors, such as weight reduction and dietary fat consumption are commonly recognized treatment modalities for NAFLD (reviewed in 13, 14). Numerous pilot studies have indicated that insulin sensitizers such as thiazolidinediones and antioxidants such as vitamin E improve clinical and histological features of NASH (15-21). Because of the lack of larger clinical trials, the value of these drugs for the treatment of NASH remains uncertain.